This application will support a 5 year mentored patient-oriented research career development award (K23) for Jakub K. Simon, M.D., to become an independent researcher in vaccinology. It will provide Dr. Simon the support, training, and mentoring to contribute to the identification of novel immunologic correlates of protection in shigellosis. Shigella is an intracellular Gram-negative bacillus that infects 165 million people per year and kills over 1 million, most of whom are children less than 5 years of age in the developing world. Natural immunity occurs, and promising candidate vaccines have been developed. The correlates of long-term protection in natural and vaccine-induced immunity are only partially defined, however, a fact that has delayed the development of effective vaccines. The long-term objective of this research is to contribute to the identification of immunologic correlates of protection in shigellosis with the ultimate goal to accelerate Shigella vaccine development. Specific Aim 1: Expand a currently active case control study in Colina, Chile, to include blood draws to isolate cells and serum as well as stool immunology to compare the immune response to Shigella infection of symptomatic cases with asymptomatically infected controls. Specific aim 2: Perform a challenge study with homologous Shigella flexneri 2a as well as heterologous Shigella flexneri 3a serotypes in healthy adult volunteers previously vaccinated with Shigella flexneri 2a candidate vaccine and compare the immune response of symptomatic and asymptomatic individuals. By comparing the immune response of symptomatic and asymptomatic individuals infected with Shigella, we will be able to assess our hypothesis that the mechanism for immunologic protection in Shigella infection is primarily mediated by fecal IgA secretion and Shigella-specific interferon (IFN)-gamma production.